Animals and humans self-administer the same classes of drugs and such self-administration defines these drugs as positive reinforcers. It is well established that the dopaminergic system plays an important role in reward-related behaviours, and drugs with reinforcing properties share the ability to increase levels of dopamine in terminal areas. Neurotransmitters mediate their effects via receptors called G-protein coupled receptors (GPCRs). It is also generally agreed that certain neurotransmitters also have a significant effect on the actions of drugs of abuse via modulations of dopamine transmission. It is therefore important to understand how these neurotransmitters, especially serotonin, glutamate and adenosine, exert their intracellular actions. Structurally, GPCRs are trans membrane proteins exhibiting a large extra cellular region that allows them to respond to external stimuli and transmit them to downstream effectors via their intra cellular regions. These effector messages converge to several major pathways, such as the dopaminergic/ DARPP-32 pathway. To get a better understanding of how these different GPCRs modulate the effects of drugs of abuse, it is crucial to understand how their associated proteins function. We have identified candidate proteins that interact with the three classes of receptors and we propose to study these proteins to elucidate their actions with drugs of abuse. We have chosen one protein for each class of the three receptors mentioned above. Specific Aim I will be to study the role of SKIP, a novel serotonin receptor interacting protein, in the actions of psychostimulants. Specific Aim II will to study the role of mGluRS.bpl, a novel metabotropic glutamate receptor interacting protein, in the actions of psychostimulants. And finally the Specific Aim III will be to study the role of A2AR-FGFR heterodimer formation and ERK pathway activation in the actions of psychostimulants. Taken together, these studies will provide detailed information on how GPCRs modulating dopamine neurotransmission can influence drugs of abuse and the effects of psychostimulants.